Clinical practice guideline on diagnosis and treatment of hyponatraemia

CLINICAL PRACTICE GUIDELINE ON DIAGNOSIS

AND TREATMENT OF HYPONATRAEMIA

February 2014

Hierarchy of Outcomes

Formulating statements and grading recommendations

Method of rating the quality of the evidence


Method of rating the quality of the evidence. Adapted from Balshem H, Helfand M, Schu¨ nemann HJ, Oxman AD, Kunz R,Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of ClinicalEpidemiology 2011 64 401–406.

Grade of the overall quality of evidence


Grade for the overall quality of evidence. Adapted from Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y,Alonso-Coello P, Schu¨ nemann HJ & GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008 336 924–926

Implications of strong and weak recommendations for stakeholders


Implications of strong and weak recommendations for stakeholders. Adapted from Guyatt GH, Oxman AD, Kunz R, Falck- Ytter Y, Vist GE, Liberati A, Schunemann HJ & GRADE Working Group. Going from evidence to recommendations. BMJ 2008 3361049–1051. The additional category ‘Not Graded’ was used, typically, to provide guidance based on common sense or where thetopic does not allow adequate application of evidence. The most common examples include recommendations regardingmonitoring intervals, counselling and referral to other clinical specialists. The ungraded recommendations are generally written assimple declarative statements but are not meant to be interpreted as being stronger recommendations than level 1 or 2recommendations.

Grade system for grading recommendations


Grade system for grading recommendations. Adapted from Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schunemann HJ & GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008 336 924–926.

6. Diagnosis of Hyponatraemia

6.1. Classification of hyponatraemia


6.1.1. Definition of hyponatraemia based on biochemical severity

6.1.1.1. We define ‘mild’ hyponatraemia as a biochemical finding of a serum sodium concentration between130 and 135 mmol/l as measured by ion-specific electrode.

6.1.1.2. We define ‘moderate’ hyponatraemia as a biochemical finding of a serum sodium concentrationbetween 125 and 129 mmol/l as measured by ionspecific electrode.

6.1.1.3. We define ‘profound’ hyponatraemia as a biochemical finding of a serum sodium concentration<125 mmol/l as measured by ion-specific electrode


6.1.2. Definition of hyponatraemia based on time of development

6.1.2.1. We define ‘acute’ hyponatraemia as hyponatraemia that is documented to exist <48 h.

6.1.2.2. We define ‘chronic’ hyponatraemia as hyponatraemia that is documented to exist for at least 48 h.

6.1.2.3. If hyponatraemia cannot be classified, we consider it being chronic, unless there is clinical or anamnesticevidence of the contrary (Table 8).


Drugs and conditions associated with acute hyponatraemia (<48 h)


6.1.3. Definition of hyponatraemia based on symptoms

6.1.3.1. We define ‘moderately symptomatic’ hyponatraemia as any biochemical degree of hyponatraemia in thepresence of moderately severe symptoms of hyponatraemia (Table 5).

6.1.3.2. We define ‘severely symptomatic’ hyponatraemia as any biochemical degree of hyponatraemia in the presence of severe symptoms of hyponatraemia (Table 5).


6.2. Confirming hypotonic and excluding non-hypotonic hyponatraemia

6.2. Confirming hypotonic and excluding non-hypotonic hyponatraemia6.2.1.1. We recommend excluding hyperglycaemic hyponatraemia by measuring the serum glucose concentration and correcting the measured serum sodium concentration for the serum glucose concentration if the latter is increased (1D).


6.2. Confirming hypotonic and excluding non-hypotonic hyponatraemia6.2.1.2. Hyponatraemia with a measured osmolality <275 mOsm/kg always reflects hypotonic yponatraemia (not graded).

6.2.1.3. Accept as ‘hypotonic hyponatraemia’ a hyponatraemia without evidence for causes of non-hypotonic hyponatraemia as listed in Table 10 (not graded).


6.3. Which parameters to be used for differentiating causes of hypotonic

hyponatraemia?

6.3. Which parameters to be used for differentiating causes of hypotonic hyponatraemia?6.3.1.1. We recommend interpreting urine osmolality of a spot urine sample as a first step (1D).

6.3.1.2. If urine osmolality is %100 mOsm/kg, we recommend accepting relative excess water intake as acause of the hypotonic hyponatraemia (1D).

6.3.1.3. If urine osmolality is O100 mOsm/kg, we recommend interpreting the urine sodium concentration on a spot urine sample taken simultaneously with a blood sample (1D).

6.3. Which parameters to be used for differentiating causes of hypotonic hyponatraemia?

6.3. Which parameters to be used for differentiating causes of hypotonic hyponatraemia?6.3.1.4. If urine sodium concentration is %30 mmol/l, we suggest accepting low effective arterial volume as a cause of the hypotonic hyponatraemia (2D).

6.3.1.5. If urine sodium concentration O30 mmol/l, we suggest assessing extracellular fluid status and use of diuretics to further differentiate likely causes of hyponatraemia (2D).

6.3.1.6. We suggest against measuring vasopressin for confirming the diagnosis of SIADH (2D).

6.3. Which parameters to be used for differentiating causes of hypotonic hyponatraemia?

Essential criteria Effective serum osmolality < 275 mOsm/kg

Urine osmolality > 100 mOsm/kg at some level of decreased effective osmolality

Clinical euvolaemia

Urine sodium concentration > 30 mmol/L with normal dietary salt and water intake

Absence of adrenal, thyroid, pituitary or renal insufficiency

No recent use of diuretic agents

Supplemental criteria Serum uric acid < 0.24 mmol/L (< 4 mg/dL)

Serum urea < 3.6 mmol/L (< 21.6 mg/dL)

Failure to correct hyponatraemia after 0.9% saline infusion

Fractional sodium excretion > 0.5%

Fractional urea excretion > 55%

Fractional uric acid excretion > 12%

Correction of hyponatraemia through fluid restriction

Table 6| Diagnostic criteria for the syndrome of inappropriate antidiuresisAdapted from Schwartz WB et al. Am J Med 1957; 23: 529-543. [29] and Janicic N et al. Endocrinol Metab Clin North Am 2003; 32: 459-481. [244]

Malignant diseases

Pulmonary disorders Disorders of the nervous system

Drugs Other causes

Carcinoma Lung Oropharynx Gastro-intestinal tract stomach duodenum pancreas Genitourinary tract ureter bladder prostate endometrium Endocrine thymomaLymphomasSarcomas Ewing’s sarcomaOlfactory neuroblastoma

InfectionsBacterial pneumoniaViral pneumoniaPulmonary abscessTuberculosisAspergillosisAsthmaCystic fibrosisRespiratory failure associated with positive-pressure breeding

InfectionEncephalitisMeningitisBrain abscessRocky Mountain spotted feverAIDSMalariaVascular and massesSubdural hematomaSubarachnoid haemorrhageStrokeBrain tumoursHead traumaOtherHydrocephalusCavernous sinus thrombosisMultiple sclerosisGuillain-Barré syndromeShy-Drager syndromeDelirium tremensAcute intermittent porphyria

Vasopressin release or action stimulantsAntidepressants -SSRIs -Tricyclic -MAOI-VenlafaxineAnticonvulsants-Carbamazepine-Oxacarbamazepine-Sodium valproate-LamotrigineAntipsychotics-Phenothiazides-ButyrophenonesAnticancer drugs-Vinca alkaloids-Platinum compounds- Ifosfamide-Melphalan-Cyclophosphamide-Methotrexate-PentostatinAntidiabetic drugs-Chlorpropamide-TolbutamineMiscellaneous-Opiates-MDMA (XTC)-Levamisole-Interferon-NSAIDs-Clofibrate-Nicotine-Amiodarone-Proton pump inhibitors-Monoclonal antibodies Vasopressin analoguesDesmopressinOxytocinTerlipressinVasopressin

HereditaryGain-of-function mutation of the vasopressin V2 receptorIdiopathicTransientExercise-associated hyponatraemiaGeneral anesthesiaNauseaPainStress

Table 7| Causes of the syndrome of inappropriate antidiuresis

SIADH Cerebral salt wasting

Serum urea concentration Normal – low Normal – high

Serum uric acid concentration Low Low

Urine volume Normal – low High

Urine sodium concentration > 30 mmol/L >> 30 mmol/L

Blood pressure Normal Normal – orthostatic hypotension

Central venous pressure Normal Low

Table 11| Differences between SIADH and cerebral salt wastingAdapted from Sherlock M et al. Clin Endocrinol 2006; 64: 250-254 [42] .

7. Treatment of Hypotonic Hyponatraemia

7.Treatment of Hypotonic Hyponatraemia

7.1. Hyponatraemia with severe symptoms


7.1.1. First-hour management, regardless of whether hyponatraemia is acute or chronic7.1.1.1. We recommend prompt i.v. infusion of 150 ml 3% hypertonic for 20 min (1D).

7.1.1.2. We suggest checking the serum sodium concentration after 20 min while repeating an infusion of 150 ml 3% hypertonic saline for the next 20 min (2D).

7.1.1.3. We suggest repeating therapeutic recommendations 7.1.1.1 and 7.1.1.2 twice or until a target of 5 mmol/l increase in serum sodium concentration is achieved (2D).


7.1.1. First-hour management, regardless of whether hyponatraemia is acute or chronic

7.1.1.4. Manage patients with severely symptomatic hyponatraemia in an environment where close biochemical and clinical monitoring can be provided (not graded).


7.1.2. Follow-up management in case of improvement of symptoms after a 5 mmol/l increase in serum sodium concentration in the first hour, regardless of whether hyponatraemia is acute or chronic7.1.2.1. We recommend stopping the infusion of hypertonic saline (1D).

7.1.2.2. We recommend keeping the i.v. line open by infusing the smallest feasible volume of 0.9% saline until cause-specific treatment is started (1D).

7.1.2.3. We recommend starting a diagnosis-specific treatment if available, aiming at least to stabilise sodium concentration (1D).


7.1.2. Follow-up management in case of improvement of symptoms after a 5 mmol/l increase in serum sodium concentration in the first hour, regardless of whether hyponatraemia is acute or chronic7.1.2.4. We recommend limiting the increase in serum sodium concentration to a total of 10 mmol/l during the first 24 h and an additional 8 mmol/l during every 24 h thereafter until the serum sodium concentration reaches 130 mmol/l (1D).

7.1.2.5. We suggest checking the serum sodium concentration after 6 and 12 h and daily afterwards until the serum sodium concentration has stabilised under stable treatment (2D).


7.1.3. Follow-up management in case of no improvement of symptoms after a 5 mmol/l increase in serum sodium concentration in the first hour, regardless of whether hyponatraemia is acute or chronic.7.1.3.1. We recommend continuing an i.v. infusion of 3% hypertonic saline or equivalent aiming for anadditional 1 mmol/l per h increase in serum sodium concentration (1D).

7.1.3.2. We recommend stopping the infusion of 3% hypertonic saline or equivalent when the symptomsimprove, the serum sodium concentration increases 10 mmol/l in total or the serum sodium concentration reaches 130 mmol/l, whichever occurs first (1D).


7.1.3. Follow-up management in case of no improvement of symptoms after a 5 mmol/l increase in serum sodium concentration in the first hour, regardless of whether hyponatraemia is acute or chronic.7.1.3.3. We recommend additional diagnostic exploration for other causes of the symptoms than hyponatraemia (1D).

7.1.3.4. We suggest checking the serum sodium concentration every 4 h as long as an i.v. infusion of 3%hypertonic saline or equivalent is continued (2D).


7.2. Hyponatraemia with moderately severe symptoms



7.2.1.1. We recommend starting prompt diagnostic assessment (1D).

7.2.1.2. Stop, if possible, medications and other factors that can contribute to or provoke hyponatraemia (not graded).

7.2.1.3. We recommend cause-specific treatment (1D).

7.2.1.4. We suggest immediate treatment with a single i.v. infusion of 150 ml 3% hypertonic saline or equivalent over 20 min (2D).


7.2. Hyponatraemia with moderately severe symptoms7.2.1.5. We suggest aiming for a 5 mmol/l per 24 h increase in serum sodium concentration (2D).

7.2.1.6. We suggest limiting the increase in serum sodium concentration to 10 mmol/l in the first 24 h and 8 mmol/l during every 24 h thereafter, until a serum sodium concentration of 130 mmol/l is reached (2D).

7.2.1.7. We suggest checking the serum sodium concentration after 1, 6 and 12 h (2D).



7.2.1.8. We suggest additional diagnostic exploration for other causes of the symptoms if the symptomsdo not improve with an increase in serum sodium concentration (2D).

7.2.1.9. We suggest considering to manage the patient as in severely symptomatic hyponatraemia if the serum sodium concentration further decreases despite treating the underlying diagnosis (2D).


7.3. Acute hyponatraemia without severe or moderately severe symptoms


7.3. Acute hyponatraemia without severe or moderately severe symptoms7.3.1.1. Make sure that the serum sodium concentration has been measured using the same technique used for the previous measurement and that no administrative errors in sample handling have occurred (not graded).

7.3.1.2. If possible, stop fluids, medications and other factors that can contribute to or provoke hyponatraemia (not graded).

7.3.1.3. We recommend starting prompt diagnostic assessment (1D).


7.3. Acute hyponatraemia without severe or moderately severe symptoms7.3.1.4. We recommend cause-specific treatment (1D).

7.3.1.5. If the acute decrease in serum sodium concentration exceeds 10 mmol/l, we suggest a single i.v. Infusion of 150 ml 3% hypertonic saline or equivalent over 20 min (2D).

7.3.1.6. We suggest checking the serum sodium concentration after 4 h, using the same technique as used for the previous measurement (2D).


7.4. Chronic hyponatraemia without severe or moderately severe

symptoms


7.4. Chronic hyponatraemia without severe or moderately severe symptoms 7.4.1. General management

7.4.1.1. Stop non-essential fluids, medications and otherfactors that can contribute to or provoke hyponatraemia(not graded).

7.4.1.2. We recommend cause-specific treatment (1D).

7.4.1.3. In mild hyponatraemia, we suggest against treatmentwith the sole aim of increasing the serum sodium concentration (2C).


7.4. Chronic hyponatraemia without severe or moderately severe symptoms 7.4.1. General management

7.4.1.4. In moderate or profound hyponatraemia, we recommendavoiding an increase in serum sodium concentration of O10 mmol/l during the first 24 h and O8 mmol/l during every 24 h thereafter (1D).

7.4.1.5. In moderate or profound hyponatraemia, we suggestchecking the serum sodium concentration every 6 h until the serum sodium concentration has stabilised under stable treatment (2D).

7.4.1.6. In case of unresolved hyponatraemia, reconsider thediagnostic algorithm and ask for expert advice (not graded).


7.4. Chronic hyponatraemia without severe or moderately severe symptoms 7.4.2. Patients with expanded extracellular fluid

7.4.2.1. We recommend against a treatment with the sole aimof increasing the serum sodium concentration in mild or moderate hyponatraemia (1C).

7.4.2.2. We suggest fluid restriction to prevent further fluidoverload (2D).

7.4.2.3. We recommend against vasopressin receptorantagonists (1C).

7.4.2.4. We recommend against demeclocycline (1D).


7.4. Chronic hyponatraemia without severe or moderately severe symptoms 7.4.3. Patients with SIAD

7.4.3.1. In moderate or profound hyponatraemia, we suggestrestricting fluid intake as first-line treatment (2D).

7.4.3.2. In moderate or profound hyponatraemia, we suggestthe following can be considered equal secondline treatments: increasing solute intake with 0.25–0.50 g/kg per day of urea or a combination of low-dose loop diuretics and oral sodiumchloride (2D).

7.4.3.3. In moderate or profound hyponatraemia, we recommendagainst lithiumor demeclocycline (1D).


7.4. Chronic hyponatraemia without severe or moderately severe symptoms 7.4.3. Patients with SIAD

7.4.3.4. In moderate hyponatraemia, we do not recommendvasopressin receptor antagonists (1C).

7.4.3.5. In profound hyponatraemia, we recommend againstvasopressin receptor antagonists (1C).


7.4. Chronic hyponatraemia without severe or moderately severe symptoms 7.4.4. Patients with reduced circulating volume

7.4.4.1. We recommend restoring extracellular volume withi.v. infusion of 0.9% saline or a balanced crystalloid solution at 0.5–1.0 ml/kg per h (1B).

7.4.4.2. Manage patients with haemodynamic instability in an environment where close biochemical and clinical monitoring can be provided (not graded).

7.4.4.3. In case of haemodynamic instability, the need for rapid fluid resuscitation overrides the risk of an overly rapid increase in serum sodium concentration (not graded).


7.5. What to do if hyponatraemia is corrected too rapidly?

7.5.1.1. We recommend prompt intervention for re-loweringthe serum sodium concentration if it increases O10 mmol/l during the first 24 h or O8 mmol/l in any 24 h thereafter (1D).

7.5.1.2. We recommend discontinuing the ongoing active treatment (1D).

7.5.1.3. We recommend consulting an expert to discuss if it is appropriate to start an infusion of 10 ml/kg body weight of electrolyte-free water (e.g. Glucose solutions) over 1 h under strict monitoring of urine output and fluid balance (1D).


7.5. What to do if hyponatraemia is corrected too rapidly?

7.5.1.4. We recommend consulting an expert to discuss if it is appropriate to add i.v. desmopressin 2 mg, with the understanding that this should not be repeated more frequently than every 8 h (1D).


Figure 2| Adaptation of the brain to hypotonicity

Reproduced with permission from Adrogué HJ et al. New Engl J Med 2000; 342: 1581-1589.

Figure 3| Osmotic stimulation of vasopressin release

Schematic representation of normal physiological relationships among plasma osmolality, plasmaAVP concentrations, urine osmolality, and urine volume in man. Note particularly the inverse of nature of the relation between urine osmolality and urine volume, resulting in disproportionate effects of small changes in plasma AVP concentrations on urine volume at lower AVP levels. Reproduced with permission from Verbalis JG. Best Prac Res En 2003; 17: 471-503.

Figure 4| Effects of hypovolaemia on osmoreceptor gain

Reproduced with permission from Robertson GL et al. J Clin Endocr Metab 1976; 42: 613-620.

Figure 5| Pseudohyponatraemia

Normally, serum contains 7 percent solids by volume. In order to reduce the volume of blood needed for analysis, serum is frequently diluted before the actual measurement is obtained. The same volume of diluent is always used; the degree of dilution is estimated under the assumption that the serum contains 7 percent solid-phase particles. When the fraction of solid-phase particles is increased, the same amount of diluent results in a greater dilution, unbeknownst to the laboratory personnel (right side of figure). Consequently, the calculation of an ion level with the use of a degree of dilution that is based on the incorrect fraction of solid-phase particles will lead to an underestimate. Reproduced with permission from Turchin A et al. NEJM 2003; 349: 1465-1469. [92]

Diagnostic Flow chart

Management flow chart

References Nephrol. Dial. Transplant. (2014) 29 (suppl 2): i1-i39.

doi: 10.1093/ndt/gfu040

Eur J Endocrinol. 2014 Feb 25;170(3):G1-47doi: 10.1530/EJE-13-1020.

Intensive Care Med. 2014 Mar;40(3):320-31. doi: 10.1007/s00134-014-3210-2

Nephrol. Dial. Transplant Intensive Care Med. Eur J Endocrinol

Clinical practice guideline on diagnosis and treatment of hyponatraemia

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